This invention relates to decahydroisoquinoline analgesics.
Boekelheide and Schilling, J. Am. Chem. Soc. 72, 712 (1950), disclosed the compound N-methyl-4a-phenyl-decahydroisoquinoline (naming it "N-methyl-10-phenyldecahydroisoquinoline) and indicated that only one of the possible forms, presumably the cis, was present; also that it had low analgesic activity.
Finch, et. al., J. Org. Chem. 39, 8, 1118 (1974) disclosed that the compound prepared by the Boekelheide process has the trans stereochemistry.
Eddy, J. Am. Pharm. Assoc. 34, 245 (1950), in relating chemical structure to analgesic action, said that "one can see in the morphine framework a number of simpler structures [one of them decahydroisoquinoline] and it is easy to imagine that the whole molecule is built around any one of them. Each of the moieties by itself is relatively inert and completely devoid of analgesic action. Nevertheless, with everyone of them as a starting point, new compounds have been synthesized which exhibit some degree of "analgesic effect".
Brittelli and Ripka, Belgian Pat. No. 802,557, disclose N-phenethyl-4a-aryl-trans-decahydroisoquinolines, useful as analgesics.
The incorporation of an N-phenethyl substituent normally does not lead to lower addiction liability. An example of this is phenazocine (2'-hydroxy-5,9-dimethyl-2-phenethyl-6,7-benzomorphan, trade name Prinadol.RTM..) In discussing this compound Jaffe states that "although developed by May and Eddy at the National Institutes of Health, with the hope that it would be free of morphine's abuse liability, phenazocine did not fulfill this goal. The drug is a potent analgesic, but it also produces the entire range of morphine-like actions, including respiratory depression, constipation, and physical dependence." (Goodman & Gilman, the Pharmacological Basis of Therapeutics, MacMillan, 1965, p. 273). ##STR1##
Phenzaocine hydrobromide has an analgesic ED.sub.50 in mice of 0.2 mg/kg and a Straub tail ED.sub.50 of 0.5 mg/kg (Shemano and Wendel, Toxicology and Appl. Pharmacol. 6, 334 (1964)). Therefore, the ratio of Straub tail ED.sub.50 to analgesic ED.sub.50 is about 2.5. In morphine this ratio (ED.sub.50.sup.ST /ED.sub.50.sup.analgesia) is 6.3/5.6 .perspectiveto. 1. Thus, compounds that are very addictive have a low ratio.
N-phenethyl-4a-(m-hydroxyphenyl)-trans-decahydroisoquinoline (Belgian Patent 802,557) has an oral ED.sub.50.sup.ST /ED.sub.50.sup.analgesia of 10/6.6 .perspectiveto. 1.
I have found that substitution of a particular phenethyl, namely p-methylphenethyl, on the nitrogen of the 4a-aryldecahydroisoquinolines leads to compounds that are more potent as analgesics and surprisingly less potentially addicting as indicated by Straub tail. N-(p-methylphenethyl)-4a-m-hydroxyphenyl-trans-decahydroisoquinoline has an ED.sub.50.sup.ST /ED.sub.50.sup.analgesia of 93/2 = 46.